Medicine and Health Sciences Commons^™

The Adaptor Protein P66shc Governs Central Nervous System Cell Metabolism And Resistance To Aβ Toxicity, Asad Lone

Electronic Thesis and Dissertation Repository

Alzheimer’s disease (AD), a progressive and irreversible neurodegenerative disorder, and is the leading cause of dementia worldwide. It has been posited that AD is caused by the gradual deposition of toxic amyloid-b (Ab) plaques in the brain- that cause oxidative stress and eventually leads to neuronal death and synaptic loss. However, multiple therapies that either interfere with the production, or enhance the removal of Ab from the brain, have ultimately failed to slow or prevent AD. With the ever-increasing burden of AD worldwide, there exists an urgent need for novel therapeutic targets. The adult human brain is an energy demanding …

Applications Of Hair As A Record Of Systemic Exposure To Cortisol, Jeffrey Matthew Levine

Electronic Thesis and Dissertation Repository

Hair cortisol content (HCC) is a novel biomarker that uniquely captures retrospective systemic cortisol exposure. This thesis aimed to assess how different hair growth rates effect HCC timelines in Cushing’s and Addison’s patients, investigate the relationship between HCC and age, puberty, sex and BMI in healthy children and adolescents, and assess novel methods to improve cortisol extraction and recovery. Retrospective HCC timelines derived from a 0.75 cm/month growth rate best matched 50% of patients’ medical records rather than the historically assumed 1 cm/month. HCC correlated positively with age (p<0.0001), puberty status (p<0.001), and BMI (p<0.01) in males and females 7-17 years old. Nitrogen evaporation resulted in greater cortisol recovery than air evaporation (p=0.0003), and hair digestion using NaOH resulted in more rapid extraction of cortisol. These results provide incremental improvements to previous methods and assumptions for HCC analysis and elucidate normal HCC changes in children and adolescents.

Family Physician's Clinical Inertia In The Management Of Hypoglycemia, Caroline V. Martignoni Rebicki

Electronic Thesis and Dissertation Repository

Though the management of diabetes is widely documented in scientific literature, little is published about how hypoglycemia is managed by family physicians. The objective of this study was to create a measurement for family physician clinical inertia in managing hypoglycemia, and to determine family physicians’ characteristics associated with clinical inertia. The design was a secondary analysis of the data provided by 162 family physicians from the Canadian InHypo-DM Study. The outcome for this thesis was a score for physician clinical inertia. The methods applied were exploratory factor analysis, bivariate analysis and multiple linear regression. Results showed no statistically significant differences …

A Clinico-Pathological Study Of The Structural And Functional Changes In The Retina And Optic Nerve Following Diabetic Retinopathy Treatments, Richard Filek

Electronic Thesis and Dissertation Repository

Diabetic retinopathy (DR) is the result of microvascular changes in the retina due to hyperglycemia which alter the blood-retinal barrier (BRB). The increased permeability of BRB results in the accumulation of extracellular fluid, the development of diabetic macular edema (DME) and capillary occlusion. Capillary occlusion results in retinal ischemia which increases vascular endothelial growth factor (VEGF) levels, increases vascular permeability and results in neovascularization in proliferative diabetic retinopathy (PDR) patients. The treatments clinically used for DR are panretinal photocoagulation (PRP) for PDR and injectable vascular endothelial growth factor inhibitors (anti-VEGFs) for DME.

The safety of PRP and anti-VEGF therapy on …

Detection Of Circulating Thyroid Tumor Dna In Patients With Thyroid Nodules, Krupal Bhupendrabhai Patel

Electronic Thesis and Dissertation Repository

This study was conducted to determine the feasibility of detecting BRAF(V600E) circulating tumor DNA (ctDNA) in the plasma of patients with thyroid nodules, with the goal of distinguishing between benign and malignant nodules. Plasma samples from patients undergoing thyroid surgery for thyroid nodules were obtained prospectively pre-operatively and one month post-operatively, and quantitative-PCR was used determine the presence of BRAF(V600E) ctDNA. These were compared to formalin fixed paraffin embedded samples from the index nodule. Thirty-eight pairs of preoperative and postoperative plasma samples were collected and analyzed. 6/18 (33.3%) patients with classical PTC and 0/8 (0%) patients with nodular hyperplasia had …

Investigation Of Pancreatic Β-Cell Insulin Receptor Regulation Of Β-Cell Growth, Function, And Survival Via A Temporal Conditional Knockout, Liangyi Zhou

Electronic Thesis and Dissertation Repository

The expression of insulin receptor (IR) in β-cells suggests an autocrine role for insulin signalling in β-cell function and regulation. Studies have demonstrated that β-cell Ir knockout (βIrKO) mice develop age-dependent glucose intolerance. We investigated the temporal role of β-cell IR signaling in pre- and postnatal islet development and function, and under high-fat diet stress, using a tamoxifen-inducible Cre-recombinase Ir knockout mouse model.

Prenatal βIrKO mice exhibited increased mean islet area, β-cell area, and islet area percentage. Additionally, there was upregulation of insulin-like growth factor-2 levels, increased Akt activity, and increased proliferation in islets. Postnatally-induced βIrKO mice did not exhibit …

Antihyperglycemic Medications And Hypoglycemia In Older Adults With Diabetes, Kristin K. Clemens

Electronic Thesis and Dissertation Repository

Background: In the last decade, several new antihyperglycemic medications have been approved to treat people with diabetes. However, the hypoglycemia risk of these medications in older adults in routine clinical practice remains unclear. Further, there is limited understanding as to how these medications are being prescribed to older adults in our region.

Methods: We carried out retrospective, population-based studies of adults age 66 and older in Ontario, Canada using linked healthcare databases. We first investigated the real-world hypoglycemia risk of 2 antihyperglycemic medications – glyburide and modified-release gliclazide. In an ecological study, we then examined trends in antihyperglycemic medication prescriptions, …

Regulation Of Leukocyte-Derived Matrix Metalloproteinases And Azurophilic Enzymes In Human Diabetic Ketoacidosis, Martin Woo

Electronic Thesis and Dissertation Repository

Diabetic Ketoacidosis (DKA) is associated with pediatric cerebrovascular-related complications. DKA-associated inflammation instigates leukocyte adherence to the brain microvascular endothelium. As adhered leukocytes release enzymes that compromise vascular integrity, we questioned a role for leukocyte-derived matrix metalloproteinases (MMPs) and azurophilic enzymes (elastase, proteinase-3, myeloperoxidase). Our aims were to measure leukocyte-derived enzymes in DKA plasma, determine associations with DKA severity and investigate their effect on the cerebrovascular endothelium.

Plasma was obtained from children with type-1 diabetes, either in acute DKA or insulin-controlled. DKA was associated with altered plasma levels of ↓MMP-2, ↑MMP-8, ↑MMP-9 and ↑TIMP-4, which are largely leukocyte in origin. DKA …

Polycomb Repressive Complex 2 Regulates Mir-200b In Retinal Endothelial Cells: Possible Implications In Diabetic Retinopathy, Michael A. Ruiz

Electronic Thesis and Dissertation Repository

Glucose-induced augmented vascular endothelial growth factor (VEGF) production is a key event in diabetic retinopathy. We have previously demonstrated that downregulation of miR-200b increases VEGF, mediating structural and functional changes in the retina in diabetes. However, mechanisms regulating miR-200b in diabetes are not known. Histone methyltransferase complex, Polycomb Repressive Complex 2 (PRC2), has been shown to repress miRNAs in neoplastic process. We hypothesized that, in diabetes, PRC2 represses miR-200b through its histone H3 lysine-27 trimethylation mark. We show that human retinal microvascular endothelial cells exposed to high levels of glucose regulate miR-200b repression through histone methylation, and that inhibition of …

Cortisol And Testosterone In Hair As Biological Markers Of Systolic Heart Failure, Justin Chan

Electronic Thesis and Dissertation Repository

Congestive heart failure (CHF) is associated with increased stress and alterations in metabolism, favoring catabolism over anabolism. Hormonal profiles of patients with heart failure have been assessed using serum and saliva as matrices, which are only point measurements and do not provide long-term information. Scalp hair is a novel matrix that allows for measurement of hormones over a period of several months. We aimed to evaluate whether levels of cortisol and testosterone and their ratio (C/T) in hair correlate with severity of heart failure. We conducted a prospective study in ambulatory male patients with a left ventricular ejection fraction (LVEF) …

Evaluating The Impact Of Two Different Methods Of Diabetes Self-Management Education On Knowledge, Attitude, And Behaviours Of Patients With Type 2 Diabetes Mellitus, Laura B. Briden

Electronic Thesis and Dissertation Repository

This study compared the effectiveness of diabetes self-management education (DSME) methods by examining changes in knowledge, attitude, and behaviour (KAB) after receiving education. Participants from a convenience sample were randomized into two groups, one receiving education through conversation maps and the other through traditional group education. Participants’ knowledge and attitude changes were measured by using a repeated measures pre-test/post-test design and changes in Hb A1c were observed. Focus groups were conducted after education was received to obtain perceptions and self-reported behaviour changes. Significant knowledge and attitude score changes were observed in the conversation map group after education. When comparing the …

Elucidating The Function Of Transplanted Islets Of Langerhans And Predicting Their Ability To Reverse Diabetes, Andrew R. Pepper

Electronic Thesis and Dissertation Repository

Type 1 diabetics require daily injections of exogenous insulin to control hyperglycemia. Unfortunately, patients are still plagued by vascular and hypoglycemic complications. Beta cell replacement therapy by either whole organ pancreas or islet transplantation has been shown to restore carbohydrate control to these patients. A major barrier to successful islet transplantation is the lack of a reliable pre-transplant assay of post-transplant function thus providing an objective measure of whether a particular islet isolation should be transplanted. Such an assay would also prove to be a valuable tool in the experimental evaluation of innovative islet isolation strategies and technologies. The initial …

Methodological Challenges And Clinical Applications Of Hair Cortisol Analysis, Evan W. Russell

Electronic Thesis and Dissertation Repository

This thesis examines methodological and clinical aspects of hair cortisol analysis. The methodological study examines the role of sweat as a contributor to hair cortisol concentrations. Hair cortisol analysis is an effective measure of chronic stress. Cortisol is assumed to enter the hair via blood, sebum, and sweat, however the extent to which sweat contributes to hair cortisol content was unknown. This study concluded that human sweat contains cortisol that likely contributes to hair cortisol content. Subjects with prolonged sweating at the time of hair collection may have increased hair cortisol concentrations that cannot be decreased with conventional laboratory washing …